Mechanism and biology of widespread distal 3'UTR utilization in the CNS The 3' untranslated regions (3'UTRs) of messenger RNAs (mRNAs) are the predominant location of cis-regulatory sequences that mediate post-transcriptional gene regulation. 3'UTRs can impart profound positive or negative regulatory impact on gene function, via diverse RNA binding proteins (RBPs) and short RNAs termed microRNAs (miRNAs). In recent years, it has been appreciated that alternative polyadenylation (APA) can induce 3'UTR variation according to cell-state, tissue identity or environmental condition, providing a strategy for coordinate post-transcriptional regulation of hundreds of genes. However, the molecular mechanisms of APA are mostly unknown and only for a few genes have the consequences of disrupting APA been studied in intact animals. We recently described broad tissue-specific APA trends in Drosophila, including substantial 3'UTR lengthening in the central nervous system. This included hundreds of unannotated extensions, ranging into lengths unprecedented for experimentally- validated 3'UTRs of stable transcripts detected by Northern analysis. Our ongoing unpublished efforts reveal that these principles are broadly conserved in the mammalian brain. Altogether, the existence of these unexpectedly broad and long 3'UTR extensions has strong implications for gene regulation in the nervous system. In particular, we hypothesize that they mediate critical aspects of the unique post-transcriptional needs of neurons, imposed by their unusual cellular architecture. Our extensive preliminary data are the basis of diverse experimental strategies that we propose to elucidate the genomic breadth, the biological utility, and mechanistic underpinning to neural 3'UTR lengthening in Drosophila and mammalian systems. The proposed work exploits our established expertise with transcriptome analysis, miRNAs, post-transcriptional control, and neural development and function. We believe that the knowledge gained from our mechanistic and functional studies will have direct relevance for human disease. Dysfunction of the neuronal APA network may induce neurological conditions, while ectopic activation of the 3'UTR lengthening mechanism should severely distort gene regulatory networks outside of the brain. Our multi-faceted research program should illuminate these processes.

Public Health Relevance

Messenger RNAs (mRNAs) are the intermediaries between the genome and its encoded proteins, and it is critical that cells are able to have precise control over mRNAs to maintain appropriate gene expression. The regulatory regions of mRNA often reside on the transcript portion that follows the protein-coding region, namely within 3' untranslated regions (3'UTRs). There is extensive evidence that 3'UTRs influence mRNA stability, localization, and translational capacity, by recruiting RNA binding proteins (RBPs) and microRNAs along with their associated regulatory machineries. We are studying an expected process in the nervous system that lengthens the 3'UTRs of hundreds of transcripts, thus radically altering these regulatory regions. As this process is conserved from insects to humans, we hypothesize that this ancient mechanism of gene regulation is critical for appropriate gene activity in the nervous system. We propose an integrated set of genomewide, genetic, and biochemical approaches to dissect the biology and mechanism of neural 3'UTR lengthening, using both Drosophila and mammalian model systems. The findings from this proposal will have significant impact on revising the annotation of the human genome and will illuminate regulatory processes that are likely to be aberrant in neurological diseases and potentially in cancer.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Molecular Neurogenetics Study Section (MNG)
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Riddle, Robert D
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Sloan-Kettering Institute for Cancer Research
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